Protein Acetylation-dependent Control of Metabolic Remodeling in Heart Failure with Preserved Ejection Fraction (HFpEF)

提案摘要 射血分数正常的心力衰竭（HFpEF）占所有心脏病患者的约50%， 失败，并且与显著的发病率、死亡率和卫生保健费用相关。还没有 已经确定了HFpEF的有效治疗方法。通常与其他代谢产物共存 HFpEF被认为是全身代谢性疾病的心血管表现， 扰动然而，对其潜在机制知之甚少。我们的实验室最近 开发并验证了一种新的小鼠模型，该模型忠实地再现了大多数临床特征 人类HFpEF使用这个模型，我们发现了显著的心肌线粒体形态学 变化表明可能的功能障碍，一个潜在的共同途径连接代谢窘迫与 心功能不全因此，目前的建议旨在确定特定的线粒体缺陷 HFpEF心肌的代谢变化及其机制。我们的初步 数据表明HFpEF线粒体具有脂肪酸氧化（FAO）的特定缺陷， 其伴随着显著的线粒体蛋白质超乙酰化。进一步研究 建议测试是否超乙酰化的关键粮农组织酶，一个已知的机制，损害 FAO在其他代谢性疾病中也发挥作用。考虑到蛋白质乙酰化是 这是一个可逆的过程，我们将在体外和体内测试是否有药理学药物， 逆转蛋白质高乙酰化减轻线粒体功能障碍并改善心脏功能。 总的来说，这些研究将为线粒体代谢缺陷提供重要的见解 HFpEF的特征。通过关注可逆的蛋白质乙酰化， 立即进行临床转化此外，这项工作将作为未来的关键平台， HFpEF发病机制的研究和我的培训的下一阶段。

Proposal Summary Heart failure with preserved ejection fraction (HFpEF) accounts for ≈50% of all patients with heart failure, and is associated with significant morbidity, mortality and health care expenses. Yet no effective treatment for HFpEF has been identified. Commonly coexisting with other metabolic diseases, HFpEF is considered as the cardiovascular manifestation of a systemic metabolic disturbance. However, little is known about its underlying mechanisms. Our laboratory recently developed and validated a novel mouse model that faithfully recapitulates most clinical features of human HFpEF. Using this model, we discovered significant myocardial mitochondrial morphology changes indicating possible dysfunction, a potential common pathway linking metabolic distress with cardiac dysfunction. Therefore, the current proposal aims to identify specific mitochondrial defects and metabolic changes in HFpEF myocardium and their underlying mechanisms. Our preliminary data suggest that HFpEF mitochondria harbor a specific defect in fatty acid oxidation (FAO), which is accompanied by significant mitochondrial protein hyperacetylation. Further study is proposed to test whether hyperacetylation of key FAO enzymes, a known mechanism that impairs FAO in other metabolic diseases, also play a role in HFpEF. Given the fact that protein acetylation is a reversible process, we will test both in vitro and in vivo whether pharmacological agents that reverse protein hyperacetylaition attenuate mitochondrial dysfunction and improve cardiac function. Collectively, these studies will provide important insights into the mitochondrial metabolic defects characteristic of HFpEF. By focusing on reversible protein acetylation, the findings will have potential for immediate clinical translation. Furthermore, this work will serve as a critical platform for future mechanistic studies of HFpEF pathogenesis and for the next stages of my training.